U.S. patent application number 11/552419 was filed with the patent office on 2008-04-24 for novel compounds and preparation for montelukast sodium.
This patent application is currently assigned to Formosa Laboratories, Inc.. Invention is credited to Jui-Te Hung, Ching-Peng Wei.
Application Number | 20080097104 11/552419 |
Document ID | / |
Family ID | 39318808 |
Filed Date | 2008-04-24 |
United States Patent
Application |
20080097104 |
Kind Code |
A1 |
Hung; Jui-Te ; et
al. |
April 24, 2008 |
Novel Compounds and Preparation for Montelukast Sodium
Abstract
This invention relates to novel compounds and a process for
preparation of montelukast sodium.
Inventors: |
Hung; Jui-Te; (Taoyuan,
TW) ; Wei; Ching-Peng; (Taoyuan, TW) |
Correspondence
Address: |
WPAT, PC;INTELLECTUAL PROPERTY ATTORNEYS
2030 MAIN STREET, SUITE 1300
IRVINE
CA
92614
US
|
Assignee: |
Formosa Laboratories, Inc.
Taoyuan
TW
|
Family ID: |
39318808 |
Appl. No.: |
11/552419 |
Filed: |
October 24, 2006 |
Current U.S.
Class: |
546/180 |
Current CPC
Class: |
C07D 215/18 20130101;
C07D 405/12 20130101 |
Class at
Publication: |
546/180 |
International
Class: |
C07D 215/18 20060101
C07D215/18 |
Claims
1. A process for preparing montelukast sodium, which comprises
reacting sodium alkoxide with montelukast acid in an organic
solvent, wherein montelukast acid is obtained by acidification of
montelukast cyclohexylamine.
2. The process according to claim 1, wherein sodium alkoxide is
sodium methoxide.
3. The process according to claim 1, wherein montelukast
cyclohexylamine is in a form of crystalline salt.
4. The process according to claim 3, wherein the salt provides
montelukast acid.
5. The process according to claim 1, wherein the organic solvent is
tetrahydrofuran (THF) or methanol.
6. The process according to claim 1, which further comprises (i)
removing the organic solvent; (ii) adding water to form an aqueous
solution; and (iii) drying the aqueous solution to produce
montelukast sodium in an amorphous form.
7. The process according to claim 3, wherein montelukast
cyclohexylamine is obtained by the reaction of cyclohexylamine and
montelukast acid.
8. The process according to claim 7, wherein montelukast acid is
obtained by a deprotection of the oxazoline function of a compound
of formula IV followed by acidification. ##STR00009##
9. The process according to claim 8 wherein the deprotection is
made by a base in an organic solvent.
10. The process according to claim 9 wherein the base is sodium
hydroxide.
11. The process according to claim 9 wherein the organic solvent is
ethylene glycol.
12. The process according to claim 8 wherein the compound of
formula IV is prepared by reacting a compound of formula III
##STR00010## with methylmagnesium halide in the presence of cerium
chloride in THF.
13. The process according to claim 12, wherein the preparation is
made with methylmagnesium halide of molar equivalents in the range
of 2.5.about.4.0.
14. The process according to claim 12, wherein the preparation is
made in the presence of cerium chloride in more than 1.0 molar
equivalent.
15. The process according to claim 12, wherein the compound of
formula III is prepared by a coupling of a compound of formula B
##STR00011## with a compound of formula II ##STR00012##
16. The process according to claim 15, wherein the coupling is
performed in the temperature range of -5.about.25.degree. C.
17. A compound which is
{1-[(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl]cyclopropyl
}methanethiol.
18. A compound of formula III which is represented as
##STR00013##
19. A compound of formula IV which is represented as
##STR00014##
20. A compound of formula V which is represented as
##STR00015##
21. The compound according to claim 20 which has a powder XRD as
shown in FIG. 4.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel compounds and a process for
preparation of montelukast sodium.
DESCRIPTION OF PRIOR ART
[0002] The chemical name of montelukast sodium is: Sodium
1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hyd-
roxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic
acid and its structure is represented as follows:
##STR00001##
[0003] Montelukast sodium is a leukotriene antagonist and inhibits
the leukotriene biosynthesis. It is a white to off-white powder
that is freely soluble in methanol, ethanol, and water and
practically insoluble in acetonitrile.
[0004] European Patent No. 480,717 discloses montelukast sodium and
its preparation starting with the hydrolysis of its ester
derivative to the crude sodium salt, acidification of the crude to
montelukast acid, and purification of the crude acid by column
chromatography to give montelukast acid as an oil. The resulting
crude oil in ethanol was converted to montelukast sodium by the
treatment with an equal molar aqueous sodium hydroxide solution.
After removal of the ethanol, the montelukast sodium was dissolved
in water and then freeze dried. The montelukast sodium thus
obtained is of a hydrated amorphous form as depicted in FIG. 2.
[0005] The reported syntheses of montelukast sodium, as pointed out
by the inventor in EP 737,186, are not suitable for large-scale
production, and the product yields are low. Furthermore, the final
products, as the sodium salts, were obtained as amorphous solid
which are often not ideal for pharmaceutical formulation.
Therefore, they discloses an efficient synthesis of montelukast
sodium by the use of
2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonylox-
ypropyl)phenyl)-2-propanol to couple with the dilithium salt of
1-(mercaptomethyl)cyclopropaneacetic acid. The montelukast acid
thus obtained is converted to the corresponding dicyclohexylamine
salt and recrystallized from a mixture of toluene and acetonitrile
to obtain crystalline montelukast sodium. This process provides
improved overall product yield, ease of scale-up, and the product
sodium salt in crystalline form.
[0006] According to the process described in EP 737,186, the
chemical as well as optical purities of montelukast sodium depends
very much on the reaction conditions for the mesylation of the
quinolinyl diol with methanesulfonyl chloride. For instance, the
reaction temperature determinates the chemical purity of the
resulting coupling product montelukast lithium, due to the fact
that an increase in the reaction temperature resulted in decreased
selectivity of mesylation toward the secondary alcohol. Mesylation
of the tertiary alcohol occurred at higher temperature will
produce, especially under acidic condition, the undesired
elimination product, the styrene derivative. This styrene impurity
is difficult to remove by the purification procedure using DCHA
salt formation; while excess base, butyl lithium in this case,
present in the reaction mixture causes the formation of a
cyclization by-product, which will eventually reduce the product
yield.
[0007] PCT WO 2005/105751 discloses an alternative process for
preparing montelukast sodium by the coupling of the same mesylate
as disclosed in '186 patent with 1-(mercaptomethyl)cyclopropane
alkyl ester in the presence of a base. In this patent, the base
butyl lithium, a dangerous and expensive reagent, is replaced with
other milder organic or inorganic base. However, the problem
concerning the formation of the styrene impurity is still not
resolved.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 shows the synthesis of the present invention.
[0009] FIG. 2 illustrates the XRPD of amorphous montelukast sodium
obtained by the freeze-drying method.
[0010] FIG. 3 illustrates the XRPD of amorphous montelukast sodium
obtained by the current spray drying method.
[0011] FIG. 4 illustrates the XRPD of crystalline montelukast
cyclohexylamine.
SUMMARY OF THE INVENTION
[0012] The present invention provides a process for preparing
montelukast sodium, which comprises reacting sodium alkoxide with
montelukast acid in an organic solvent, wherein montelukast acid is
obtained by acidification of montelukast cyclohexylamine.
[0013] The present invention also provides a novel compound
{1-[(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl]cyclopropyl}methanet-
hiol.
[0014] The present invention further provides novel compounds of
formulae III, IV and V.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention provides a novel process for the
preparation of montelukast sodium free of styrene and lactone
impurities, and an overall yield comparable with that disclosed in
EP 737,186. Also, the present invention provides a process without
isolation of the unstable mesylate and an easier operation on the
subsequent coupling reaction at higher reaction temperature. The
deprotection of the oxazoline function provides a crude montelukast
sodium. After acidic work-up, a crude montelukast acid is obtained
and is purified by the formation and crystallization of its
corresponding cyclohexylamine salt. The crystalline salt is freed
to provide an acid and is re-dissolved in THF or methanol and is
then converted to montelukast sodium by the treatment with an equal
molar sodium methoxide. After distillation to remove most solvents,
the crude is diluted with water and then spray-dried to afford
montelukast sodium in an amorphous form as depicted in FIG. 3.
[0016] Accordingly, the present invention provides a process for
preparing montelukast sodium, which comprises reacting sodium
alkoxide with montelukast acid in an organic solvent, wherein
montelukast acid is obtained by acidification of montelukast
cyclohexylamine salt.
[0017] In the process of the present invention, sodium alkoxide is
not limited but can be selected from the group consisting of sodium
methoxide, sodium ethoxide, sodium propoxide, and sodium butoxide.
In the preferred embodiment, the sodium alkoxide used is sodium
methoxide.
[0018] In the process of the present invention, montelukast
cyclohexylamine is not limited but to in a form of crystalline
salt, which provides montelukast acid. In the process of the
present invention, the organic solvent is not limited but selected
from tetrahydrofuran (THF) or methanol.
[0019] To facilitate drying of montelukast sodium, the process of
the present invention further comprises (i) removing the organic
solvent; (ii) adding water to form an aqueous solution; and (iii)
drying the aqueous solution to produce montelukast sodium in an
amorphous form.
[0020] In the process of the present invention, montelukast
cyclohexylamine is obtained by the reaction of cyclohexylamine and
montelukast acid, and the above montelukast acid is obtained by a
deprotection of the oxazoline function of compound of formula IV
followed by acidification.
##STR00002##
[0021] In a preferred embodiment, the deprotection is made by a
base (such as sodium hydroxide) in an organic solvent (such as
ethylene glycol).
[0022] In the process of the present invention, the compound of
formula IV is prepared by reacting a compound of formula III
##STR00003##
with methylmagnesium halide in the presence of cerium chloride in
THF.
[0023] In a preferred embodiment, the preparation is made with the
addition of methylmagnesium halide in the range of 2.5.about.4.0
equivalents and in the presence cerium chloride in more than 1.0
equivalent.
[0024] In the process of the present invention, the compound of
formula III is prepared by the coupling of a compound of formula
B
##STR00004##
with a compound of formula II.
##STR00005##
[0025] In a preferred embodiment, the coupling is performed in the
temperature range of -5.about.25.degree. C.
[0026] The present invention also provides
{1-[(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl]cyclopropyl}methanet-
hiol.
[0027] The present invention further provides a compound of formula
III which is represented as
##STR00006##
[0028] The present invention further provides a compound of formula
IV which is represented as
##STR00007##
[0029] The present invention further provides a compound of formula
V which is represented as
##STR00008##
[0030] The compound of formula V has a powder XRD as shown in FIG.
4.
EXAMPLE
[0031] The examples below are non-limiting and are merely
representative of various aspects and features of the present
invention.
Example 1
[0032] Preparation of mesylate II and oxazoline III: In a reactor
equipped with mechanic stirrer, thermocouple, and feeding tank was
charged under nitrogen with a wet cake of compound I in toluene (11
parts). After azeotropic distillation (6 parts), the mixture was
sampled for water content test (KF<0.1%). To the resulting
mixture after cooling to room temperature was added DMF (1.7 parts)
and triethylamine (2 equiv.). When the addition was complete, the
reactor was cooled to -5.about.5.degree. C. Methanesulfonyl
chloride (1.5 equiv.) diluted with toluene (2 parts) in the feeding
tank was added dropwise and the pot temperature controlled in the
range of -5.0.about.5.0.degree. C. during the addition. After the
addition was complete, the mixture was kept stirring at
-5.0.about.5.0.degree. C. until mesylation was complete. During
this time into another SS reactor was charged under nitrogen
toluene (2 parts), DMF (0.5 parts), sodium hydride (60%, 3.0
equiv.), and oxazoline B (1.2 equiv.) while keeping the pot
temperature below 20.0.degree. C. The mesylate in the GL reactor
was added through a pipeline to the SS reactor containing the
sodium salt of oxazoline B. Two hours after the addition, the
mixture was sampled and analyzed by HPLC (compound III>95.0%).
The reaction mixture was quenched with chilled water (5 parts), and
the organic layer is separated and washed with brine. The organic
layer was concentrated until dryness to afford compound III as an
oil in 80.about.96% yield (see Table 1). .sup.1H NMR (600 MHz,
CDCl.sub.3).delta. 7.12.about.7.97 (15 H, Ar), 3.84 (t, J=7.3 Hz,
SCH, 1 H), 3.76 (s. CH.sub.2O, 2 H), 3.73 (s, OCH.sub.3, 3 H), 3.00
and 2.85 (m, SCHCH.sub.2, 2 H), 2.42 and 2.39 (ABq, .sup.2J=13.0
Hz, 2 H), 2.34 and 2.29 (ABq, SCH.sub.2, .sup.2J=14.9 Hz, 2 H),
2.06.about.2.18 (m, 2 H), 1.13 (s, CH.sub.3, 6 H), 0.28.about.0.48
(m, 4 H). .sup.13C NMR (150 MHz, CDCl.sub.3): .delta. 167.8,
164.2.0, 156.8, 148.6, 143.6, 143.3, 136.4, 136.0, 135.4, 135.0,
132.0, 131.0, 130.8, 129.4, 128.9, 128.8, 128.7, 128.61, 128.58,
128.1, 127.0, 126.9, 126.0, 125.6, 119.5, (Ar), 78.7, 66.7, 51.9,
50.0, 39.2, 38.6, 34.1, 32.8, 28.4 (CH.sub.3), 17.5 (Cy-C), 12.5,
12.2 (Cy-CH.sub.2). FABMS (m/z, intensity): M.sup.+(639, 63.01%),
M.sup.+-C.sub.10H.sub.17NOS (B) (440, 8.69%), B.sup.+--H (198,
100.00%). Other conditions used to prepare compound III were listed
in Table 1.
TABLE-US-00001 TABLE 1 Conditions for the preparation of compound
III Pu- Comp. I MeSO.sub.2Cl Et.sub.3N NaH Temp. Time rity Yield
Entry (eq.) (eq.) (eq.) (eq.) (.degree. C.) (h.) (%) (%) 1 1.0 1.5
2.0 4.0 15~20 5 96 85 2 1.0 1.2 1.5 2.5 15~20 2 98 91 3 1.0 1.5 2.0
3.0 5~10 2 99 86 4 1.0 1.5 2.0 2.2 5~10 4 96 96 5 1.0 1.2 1.5 3.0
0~5 2 98 80
Example 2
[0033] Preparation of IV: In a SS reactor equipped with mechanic
stirrer, thermocouple, and feeding tank was charged under nitrogen
THF (12 parts) and anhydrous CeCl.sub.3 (2.5 equiv. KF<1.0%).
The suspension was stirred at room temperature, and methylmagnesium
chloride (3.0.about.3.5 equiv.) was added via a Teflon pump. After
the addition was complete, the mixture was stirred further for 60
min, and cooled down to 10.about.25.degree. C. Compound III in THF
was then added through the feeding tank. After the addition, the
mixture was allowed to react further for 2.about.4 h, and checked
by HPLC (compound IV>95.0%). The reactor was cooled to
5.0.about.15.0.degree. C., and water was carefully added. The
precipitated solid was centrifuged and washed with THF, and the
filtrate was concentrated to afford compound IV as an oil in
80.about.95% yield (see Table 2). .sup.1H NMR (600 MHz,
CDCl.sub.3): .delta. 7.05.about.8.00 (15 H, Ar), 3.93 (t, J=7.3 Hz,
SCH, 1 H), 3.78 (s, OCH.sub.2, 2 H), 3.15 and 2.94 (m,
SCH.sub.2CH.sub.2, 2 H), 2.43 and 2.35 (dd, 2 H), 2.33 and 2.29
(dd, 2 H), 2.16.about.2.27 (m, 2 H), 1.57 (s, 3 H), 1.56 (s, 3 H),
1.15 (s, CH.sub.3, 6 H), 0.31.about.0.49 (m, 4 H). .sup.13C NMR
(150 MHz, CDCl.sub.3): .delta. 164.6, 156.8, 148.6, 145.7, 144.0,
140.2, 136.4, 136.1, 135.5, 135.1, 131.4, 128.9, 128.7, 128.58,
128.56, 128.1, 127.03, 126.97, 126.92, 126.0, 125.62, 15.57, 125.4,
119.6 (olefinic), 78.9, 73.3, 66.8, 50.2, 39.6, 39.2, 34.0, 32.1,
32.0, 31.9, 28.42, 28.41, 17.5, 12.6, 12.3. FABMS (m/z, relative
intensity): M.sup.+(639, 68.63%), M.sup.+-H.sub.2O (621, 10.37%),
M.sup.+-B (440, 20.71%), M.sup.+-B--H.sub.2O (424, 20.71%),
B.sup.+--H (198, 93.32%).
TABLE-US-00002 TABLE 2 Reaction conditions for the preparation of
compound IV Results Comp. II CeCl.sub.3 MeMgCl THF Time Temp.
Purity Styrene Remaining Entry (eq.) (eq.) (eq.) (parts) (min.)
(.degree. C.) (%) (%) II 1 1.0 2.0 3.5 15 30 18~22 95.6 ND 0.11 2
1.0 0.5 2.5 15 60 13~17 77.1 ND 19.4 3 1.0 0.1 2.6 15 40 18~22 37.2
ND 53.2 4 1.0 1.2 2.6 15 30 18~22 80.3 ND 0.4 5 1.0 2.1 3.5 15 30
18~22 96.4 ND 0.0 6 1.0 2.1 2.5 12 120 20~25 96.5 ND 0.0
Example 3
[0034] Preparation of crude montelukast sodium: To compound IV in
ethylene glycol (10 parts) was added aqueous sodium hydroxide
solution (1.about.3 N, 2.0 equiv.), and the resulting suspension
was heated to 120.about.150.degree. C. for 12 h followed by HPLC
analysis (montelukast sodium>94.0%). The reaction mixture was
cooled to 60.about.70.degree. C. and then concentrated under vacuum
to afford montelukast sodium as an oil in 60.about.80% yield (see
Table 3). .sup.1H NMR (600 MHz, CD.sub.3OD): .delta.
6.94.about.8.44 (15 H, Ar), 3.92 (t, J=6.66 Hz, 1 H), 2.97 (dt,
J=4.68 Hz, 12.0 Hz, 1 H), 2.71 (dt, J=4.56 Hz, 12.0 Hz, 1 H), 2.53
and 2.41 (ABq, .sup.2J=12.8 Hz, 2 H), 2.28 and 2.20 (ABq,
.sup.2J=14.6 Hz, 2 H), 2.13 (m, 1 H), 2.03 (m, 1 H), 1.41 (s, 3 H),
1.40 (s, 3 H), 0.42 (m, 1 H), 0.35 (m, 1 H), 0.28 (m, 1 H), 0.20
(m, 1 H). .sup.13C NMR (150 MHz, CDCl.sub.3): .delta. 180.9
(CO.sub.2), 170.6, 158.9, 149.4, 147.2, 145.8, 141.4, 138.3, 137.9,
137.5, 137.0, 132.6, 130.6, 130.22, 130.19, 128.9, 128.4, 128.3,
128.1, 128.0, 127.4, 127.1, 126.7, 126.6, 120.97, 74.0
(ArC(CH.sub.3).sub.2OH), 51.6 (SCH), 44.8, 41.5, 41.2, 32.5, 32.0
(CH.sub.3), 18.7 (Cy-C), 13.5, 13.0 (Cy-CH.sub.2).
TABLE-US-00003 TABLE 3 Reaction conditions for the preparation of
compound V Product Comp. IV NaOH EG Time Temp. purity Entry (eq.)
(Conc. and eq.) (parts) (h) (.degree. C.) (%) 1 1.0 1 N, 2 eq. 10
25 120 97.2 2 1.0 1 N, 2 eq. 10 12 130 97.5 3 1.0 3 N, 2 eq. 10 5
150 94.0 4 1.0 4 N, 2 eq. 5 4 160 90.8 5 1.0 3 N, 2 eq. 10 3 195
62.0
Purification and drying of Montelukast sodium
Example 4
[0035] A crude oil of montelukast sodium was treated with 5%
aqueous acetic acid to a pH of 5, and then extracted with toluene.
The resulting toluene extract was washed with water. The organic
layer containing montelukast acid was treated with cyclohexylamine
(1.1.about.1.5 equiv.), and acetonitrile was added to effect
precipitation. After stirring overnight, the salt was collected by
filtration and washed with acetonitrile. The salt thus obtained was
recrystallized over toluene/hexanes or toluene/acetonitrile until
the desired purity was reached (see Table 4). The crystalline solid
was analyzed by XRPD, and the spectrum is shown in FIG. 4. .sup.1H
NMR (600 MHz, CDCl.sub.3): .delta. 7.06.about.8.04 (15 H, Ar), 6.41
(bs, cy-NH.sub.3.sup.+), 3.96 (t, J=7.08 Hz, 1 H), 3.15 (m, 1 H),
2.77.about.2.87 (m, 2 H), 2.57 and 2.51 (ABq, .sup.2J=11.1 Hz, 2
H), 2.31 and 2.27 (ABq, .sup.2J=15.0 Hz, 2 H), 2.22 (m, 1 H), 2.12
(m, 1 H), 1.95 (d, J=10.6 Hz, 2 H), 1.68 (d, J=12.9 Hz, 2 H), 1.56
(s, 3 H), 1.54 (s, 3 H), 1.28 (m, 2 H), 1.14 (m, 2 H), 1.08 (m, 2
H), 0.49 (m, 1 H), 0.42 (m, 1 H), 0.34 (m, 1 H), 0.27 (m, 1 H).
.sup.13C NMR (150 MHz, CDCl.sub.3): .delta. 179.0 (CO.sub.2),
157.0, 148.7, 145.6, 144.1, 140.5, 136.6, 136.3, 135.7, 135.4,
131.7, 129.1, 128.8, 128.7, 128.6, 128.2, 127.2, 127.1, 127.0,
126.2, 125.8, 125.7, 125.6, 119.7 (olefinic), 73.7, 50.3, 50.2,
43.7, 40.3, 40.1, 32.5, 32.1, 32.0, 31.8, 25.1, 24.7, 17.7, 13.1,
12.4.
TABLE-US-00004 TABLE 4 Recrystallization of Montelukast
cyclohexylamine. Solvent Purity Entry solvents volume by parts HPLC
% 1 Toluene, acetonitrile 5, 10 99.22 2 Toluene, acetonitrile 10,
15 99.03 3 Toluene, hexanes 15, 15 99.17 4 Toluene, hexanes 20, 10
99.25 5 Toluene, hexanes 10, 10 99.40
Example 5
[0036] Montelukast cyclohexylamine salt suspended in toluene (5
parts) was treated with aqueous acetic acid (5 parts) until a pH of
5.0.about.5.5 was reached. The organic phase was separated and
washed with water (5 parts) twice, and the resulting organic layer
was concentrated to provide a crude oil of montelukast acid. The
montelukast acid (100.0 g, 170.2 mmol) thus obtained was dissolved
in 500 mL THF, and then 78 mL of ca. 2N NaOH aqueous solution was
added under nitrogen. After stirring for several minutes, the
solvent was removed under reduced pressure at 30.degree. C. to
afford montelukast sodium as a crude oil. The crude oil was taken
up in 2.5 L water and concentrated to remove the remaining THF
until the total volume was about 2.7 L (THF remained as analyzed by
GC was 1.7%). The aqueous solution of montelukast sodium was
filtered, and its purity was determined by HPLC (99.7%). The
filtered solution was subjected to spray drying at various
conditions, and the results were listed in Table 5.
TABLE-US-00005 TABLE 5 Spray drying of montelukast sodium in
aqueous solution Feeding Outlet Results rate Inlet air air Purity
THF KF Entry mL/min (.degree. C.) (.degree. C.) HPLC % (ppm) (%)
Yield % 1 20 140 100 99.7 92 1.9 60% 2 20 150 100 99.7 89 1.7 60% 3
28 140 85 99.1 ND 2.1 60% 4 28 140 85 99.7 ND 1.6 60% 5 28 150 84
99.6 ND 2.8 67% 6 38 140 80 99.7 ND 2.7 50% a. Spray drying is
performed on Ohkawara Kakohki Co. Ltd model L-8 b. Solid content
defined as the amount of solute is 4% c. Solid obtained with bulk
density 0.16 g/mL d. Viscosity is 5.63 centistokes at 30.degree. C.
for 4% solid content e. Aqueous solution density is about 1.0 g/mL
f. Particle size distribution; d (50) = 10 .mu.m and d (90) = 30
.mu.m
Example 6
[0037] Purified montelukast acid (85 mmol) was treated with 248 mL
0.31 N (77 mmol) sodium methoxide methanol solution (previously
degassed), and additional 16.5 mL sodium methoxide was added until
a pH of 8.43 was obtained. Most of the methanol was then removed
under reduced pressure at less than 50.degree. C. Water was added
to the resulting crude oil, and the residual methanol was distilled
off. Additional water was added to a final volume of 1,060 mL. The
aqueous solution was then filtered, the residual methanol being
3.0% as determined by GC and the purity being 99.8% as determined
by HPLC. The aqueous montelukast sodium was subjected to spray
drying, and the results were listed in Table 6.
TABLE-US-00006 TABLE 6 Spray drying of montelukast sodium in
aqueous solution Feeding Inlet Results rate air Outlet air Purity
MeOH KF Entry mL/min (.degree. C.) (.degree. C.) HPLC % (ppm) (%)
Yield % 1 20 120 80~85 99.8 0.00 1.8 80% 2 30 140 78~80 99.7 0.00
2.2 90%
[0038] While the invention has been described and exemplified in
sufficient detail for those skilled in the art to make use of it,
various alternatives, modifications, and improvements should be
apparent without departing from the spirit and scope of the
invention.
[0039] One skilled in the art readily appreciates that the present
invention is well adapted to carry out the objects and obtain the
ends and advantages mentioned, as well as those inherent therein.
The processes and methods for producing them are representative of
preferred embodiments, are exemplary, and are not intended as
limitations on the scope of the invention. Modifications therein
and other uses will occur to those skilled in the art. These
modifications are encompassed within the spirit of the invention
and are defined by the scope of the claims.
[0040] It will be readily apparent to a person skilled in the art
that varying substitutions and modifications may be made to the
invention disclosed herein without departing from the scope and
spirit of the invention.
[0041] All patents and publications mentioned in the specification
are indicative of the levels of those of ordinary skill in the art
to which the invention pertains. All patents and publications are
herein incorporated by reference to the same extent as if each
individual publication was specifically and individually indicated
to be incorporated by reference.
[0042] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations, which are not specifically disclosed herein. The
terms and expressions which have been employed are used as terms of
description and not of limitation, and there is no intention that
in the use of such terms and expressions of excluding any
equivalents of the features shown and described or portions
thereof, but it is recognized that various modifications are
possible within the scope of the invention claimed. Thus, it should
be understood that although the present invention has been
specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein
disclosed may be resorted to by those skilled in the art, and that
such modifications and variations are considered to be within the
scope of this invention as defined by the appended claims.
[0043] Other embodiments are set forth within the following
claims.
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